Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro carbostyril or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2(1H)-quinolinone, is an atypical antipsychotic agent useful for the treatment of schizophrenia. Schizophrenia is a common type of psychosis characterized by delusions, hallucinations and extensive withdrawal from others. The preparation of aripiprazole and other carbostyril derivatives is described in U.S. Pat. No. 4,734,416 and U.S. Pat. No. 5,006,528. These processes do not result in the formation of well defined, reproducible forms of aripiprazole.
Aripiprazole is known in several polymorphic forms. The Proceedings of the 4th Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996) state that, aripiprazole anhydride crystals exist as anhydrous type-I crystals (conventional anhydride), anhydrous type-II crystals, and type III hydrate (conventional hydrate); the type-I crystals of aripiprazole anhydride (conventional anhydride) can be prepared by recrystallization from an ethanol solution of aripiprazole, or by heating aripiprazole hydrate at 80° C. The type-II crystals of aripiprazole anhydride can be prepared by heating conventional anhydride at 130° to 140° C. for 15 hours. Type III crystals (conventional hydrate) were recrystallized from alcoholic solvent containing up to 20% (v/v) of water.
The hygroscopicity of the conventional anhydride crystals makes them difficult to handle since costly and burdensome measures must be taken in order to ensure that they are not exposed to moisture during preparation and formulation. When exposed to moisture, the conventional anhydrous forms of aripiprazole absorb water and convert to hydrous forms such as the monohydrate. The hydrous forms of aripiprazole have the disadvantage of being less soluble than the anhydrous forms. Moreover, variation in the amount of hydrous versus anhydrous aripiprazole from batch to batch makes it difficult to meet the specifications set by drug regulatory authorities. Furthermore, the solubility of aripiprazole is pH-dependent which influence the dissolution rate.
Numerous attempts have been made to overcome these disadvantages.
To ensure appropriate dissolution of poorly soluble drugs the drugs are commonly used in particle sizes smaller 50 μm. The small particle sizes are usually obtained by energy involved processes like extensive milling, micronization or grinding.
EP 1 330 249 and EP 1 419 776 disclose polymorphic modifications of aripiprazole which are said to have reduced hygroscopicity, such as anhydride B. Anhydride B can be obtained by milling conventional hydrate to provide intermediary hydrate A (particle size less 50 μm), which is converted to aripiprazole form B by heating to 90-125° C. for 3 to 50 hours. Anhydride B can be converted to a glassy state by heating to about 170° C. and cooling to room temperature. The glassy form of aripiprazole anhydride forms aripiprazole anhydride crystals of form G upon storing. In addition to hydrate A and anhydrides B and G aripiprazole anhydride crystals of forms C to F are described.
EP 1 606 262 discloses two crystalline forms of aripiprazole and four crystalline forms of aripiprazole hydrochloride which are said to be stable over the time and to be reproducible.
WO 2005/009990 discloses crystalline forms of aripiprazole, aripiprazole methanolate and aripiprazole ethylene dichloride solvate. These crystalline forms of aripiprazole are said to be non hygroscopic and to have no tendency to convert to other forms.
WO 2004/106322 describes the preparation of polymorphic forms II, III and IV of aripiprazole. Form II is described as having a melting point of 133 to 135° C., Form III of 122 to 125° C. and Form IV of 146 to 149° C.
WO 2005/058835 discloses anhydrous aripiprazole crystalline forms I, II, VI, VIII, X, XI, XII, XIV, XIX, XX and methods for preparing the same. These forms of aripiprazole are said to be non-hygroscopic and to maintain compound stability during storage. They can be prepared directly by slurrying without heating a preexisting hydrate crystal form.
EP 1 398 040 discloses a medicinal composition prepared by dissolving or dispersing a drug like aripiprazole and a pH-independent, water-insoluble polymer in a wax-like or glycerine ester or fatty acid like low-melting-point substance or dispersing a drug in a mixture of both.
None of the above forms of aripiprazole is completely satisfactory. For instance, during approval of aripiprazole tablets in Europe and the United States the 20- and 30-mg tablets had to be redesigned because they exhibited less than complete and slower dissolution than other aripiprazole tablet strengths at pH 1.2 (see www.fda.gov/cder/foi/nda/2002/21-436_Abilify_biopharmr_P2). In spite of this effort, the manufacturer had to recall several batches of tablets due to dissolution failure (FDA, Enforcement Report 25 Aug. 2004 and 6 Jul. 2005).
As can be seen from the above, there is a strong need for aripiprazole having a stable morphology and showing defined and stable dissolution rates. Moreover, due to the poor performance of the marketed products, the development of a stable and reproducibly bioavailable formulation of aripiprazole tablets is highly desired. None of the above mentioned forms or formulations have demonstrated sufficient bioavailability.
It is an object of the invention to provide aripiprazole in morphologically stable form with good solubility in aqueous systems which can be easily prepared.